PROJECT SUMMARY When compared to the general population, U.S. Military Veterans disproportionately experience pain, especially severe pain. Indeed, pain management is one of the most common reasons Veterans seek medical assistance. The U.S. Department of Veterans Affairs (VA) and Veterans Health Administration (VHA) have continued to focus attention on chronic pain management, which has resulted in the implementation of new guidelines and systems that prioritize non-opioid treatments. Current pharmacologic alternatives to opioids for chronic pain management include: (1) topical and oral analgesics such as lidocaine, acetaminophen, and non-steroidal anti-inflammatories (NSAIDs); (2) antidepressants; (3) anticonvulsants; and (4) muscle relaxants. We and others have defined the cardiovascular toxicity of NSAIDs and opioid analgesics, but the potential toxicity of other drug classes used to treat chronic pain remains poorly defined. This is particularly important for three classes of drugs: (1) selective norepinephrine reuptake inhibitors (SNRIs) antidepressants, (2) antiepileptics, and (3) muscle relaxants. Within each drug class, duloxetine (SNRI), pregabalin (antiepileptic), and cyclobenzaprine (muscle relaxant) are among the most frequently prescribed. Usage of these three drugs has generated multiple case reports and raised specific concerns for increased risk of serious cardiovascular events. Currently, hundreds of thousands of Veterans are filling prescriptions for these drugs each year, and the use of non-opioid pain drugs is increasing. Veterans encompass a vulnerable population with high cardiovascular risk and high rates of chronic pain; thus, they are at higher risk for adverse drug effects. The overwhelming majority of Veterans with chronic pain do not have cancer or life-threatening illness, which makes the prospect of drug toxicity from long-term use a particularly important consideration. Clinical trials play a crucial role in demonstrating treatments' efficacy; however, many drugs have had unforeseen and serious side effects. Since clinical trials necessarily are limited with regard to generalizability and can be impractical, pharmacoepidemiologic studies play a critical role in our knowledge about the long-term side effects of drugs. The proposed pharmacoepidemiologic studies seek to provide critical information about the cardiovascular risks associated with three widely prescribed non-opioid medications used to treat chronic pain and frequently prescribed to Veterans in the VA health system. We will use state of the art techniques and a large database of Veterans to assemble a cohort of patients with chronic non-cancer pain. Aim 1 will define the risk for serious cardiovascular outcomes in patients taking cyclobenzaprine. Aim 2 will define the risk of serious cardiovascular events associated with the use of duloxetine. Aim 3 will define the risk of heart failure associated in patients taking pregabalin. These studies will compare those risks with the risk observed in patients with chronic pain taking two active comparators: tramadol and celecoxib. Our overarching goal to improve the health of Veterans and prevent negative side effects makes these studies an excellent fit with the VA mission.